ClinVar Miner

Submissions for variant NM_000492.4(CFTR):c.3737C>T (p.Thr1246Ile) (rs397508600)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000668850 SCV000793522 uncertain significance Cystic fibrosis 2017-08-25 criteria provided, single submitter clinical testing
Mendelics RCV000668850 SCV000886147 uncertain significance Cystic fibrosis 2020-08-13 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000781266 SCV000919178 likely pathogenic not specified 2018-05-03 criteria provided, single submitter clinical testing Variant summary: CFTR c.3737C>T (p.Thr1246Ile) results in a non-conservative amino acid change located in the ABC transporter-like (IPR003439) domain and AA+ ATPase domain (IPR003593) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.1e-06 in 245736 control chromosomes (gnomAD). The variant, c.3737C>T, has been reported in the literature in two individuals affected with Non-classic Cystic Fibrosis together with F508del (Goubau_2009, Sosnay_2017), and in one patient with CF/CBAVD (Claustres_2000). In addition, 23 patients are listed in the CFTR2 database, some of which are reported to carry the variant along with a CF-causing variant and have CF. These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported, though a study on channel dynamics suggested the Thr1246 codon is a critical residue for function (Vergani_2005). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. It was reported in publications and databases that patients with this variant and with a known CF-causing variant may or may not have CF, indicating they could have a mild phenotype occurring later in life, with a risk for developing P. Aeruginosa infections and pancreatic insufficiency (SickKids and CFTR2 databases, Sosnay_2017). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Johns Hopkins Genomics,Johns Hopkins University RCV000668850 SCV001425315 pathogenic Cystic fibrosis 2020-04-27 criteria provided, single submitter clinical testing CFTR variant associated with varying clinical consequence. See for phenotype information.

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